Compounds for treating cancer

ABSTRACT

A method of preventing, inhibiting, or treating cancer that includes contacting a cell with at least one compound of formula (Ia) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where:
         R independently represents a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, a —CN group, a hydroxyl group, a —COOR 1  group, a (C 1 -C 3 )fluoroalkyl group, a —NO 2  group, a —NR 1 R 2  group, or a (C 1 -C 3 )alkoxy group;   R′ is a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, a —NO 2  group, a (C 1 -C 3 )alkoxy group, or a —NR 1 R 2  group; and   R 1  and R 2  are a hydrogen atom or a (C 1 -C 3 )alkyl group.

This is a continuation of U.S. application Ser. No. 14/087,762 filed Nov. 22, 2013, which is a continuation of application Ser. No. 13/377,745 filed Jul. 5, 2012, which is a National Stage Application of PCT/IB2010/052560 filed Jun. 14, 2010, and claims the benefit of U.S. Provisional Application Nos. 61/186,552 filed Jun. 12, 2009 and 61/186,544 filed Jun. 12, 2009 and European Application Nos. 09305540.8 filed Jun. 12, 2009 and 09162630.9 filed Jun. 12, 2009. The entire disclosures of the prior applications are hereby incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The present disclosure is generally directed to the manufacture and use of compounds to treat cancer.

BACKGROUND OF THE INVENTION

In most cancers, mortality is not due to the primary tumor but rather to the derived metastases. This malignant progression is clinically defined by the appearance of metastatic cells. Tumor metastases are typically defined by a primary loss of cell adhesion and an increase of cell motility, which allows for invasive cell to leave the initial tumor site and colonize various target tissues.

Metastases are considered as a recurrent feature of uncontrolled malignant progression of cancer. During this process, tumor cells complete their malignant transformation by increasing their migratory capacity. Cancer cells can then disseminate and establish new tumor foci in far away sites. This event is termed “metastatic cascade,” which, as indicated immediately above, is marked by invasion of tissues around the tumor, venous or lymphatic intravasation, migration and establishment of new tumors in distant places of an organism that may escape from all innate defense mechanisms.

Because no efficient therapeutic options presently exist for the treatment or prevention of metastatic tumors, metastatic invasion a major cause of death worldwide. Due to the frequency of cancers diagnosed at the metastatic stage and the lack of viable therapeutic options at this stage of the disease, the development of molecules that specifically target metastatic invasion is crucial for a major breakthrough in cancer treatments.

The compounds and methods of use as described herein are consistent with numerous published reports during the last twenty years that demonstrate a link between changes in RNA alternative splicing and metastatic invasion, which has opened new avenues for therapeutic strategies.

SUMMARY OF THE INVENTION

As discussed in further detail below and as shown in the working examples, formula (I) and derivatives thereof are able to correct defects of alternative splicing, a mechanism closely associated with the invasive progression of metastatic. cancers. Thus, in certain aspects, the compounds described herein may be useful for preventing, inhibiting, or treating cancer.

In certain aspects, the compounds described herein further relate to a method of preventing, inhibiting or treating cancer. For example, the method can include administering an effective amount of a compound having formula (I) or any derivative thereof as described below or one of its pharmaceutically acceptable salts to a patient.

As described in greater detail below, the compounds described herein can be included in pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the subject-matter described herein relates to a compound of formula (I)

-   -   wherein:

means an aromatic ring wherein V is C or N and when V is N, V is in an ortho, meta or para position with respect to Z, i.e. forms respectively a pyridazine, a pyrimidine or a pyrazine group,

-   -   R independently represents a hydrogen atom, a halogen atom or a         group chosen among a —CN group, a hydroxyl group, a —COOR₁         group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,         a —NO₂ group, a —NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy         group and a (C₁-C₃)alkyl group, the alkyl being optionally         mono-substituted by a hydroxyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   n is 1, 2 or 3,     -   n′ is 1 or 2,     -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a morpholinyl or a morpholino group, a         N-methylpiperazinyl group, a (C₁-C₃)fluoroalkyl group, a         (C₁-C₄)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   Z is N or C,     -   Y is N or C,     -   X is N or C,     -   W is N or C,     -   T is N or C,     -   U is N or C,     -   and wherein at most four of the groups V, T, U, Z, Y, X and W         are N,     -   and at least one of the groups T, U, Y, X and W is N,     -   or anyone of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

According to one aspect, formula (I) as defined above includes a compound wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W is C, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound wherein Z is C, V is C, Y is N, X is C, T is C, U is C and W is C, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound wherein Z is N, V is C, Y is C, X is N, T is C, U is C and W is C, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound wherein Z is N, V is C, Y is C, X is C, T is C, U is C and W is N, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the para position with respect to Z, Y is N, X is C, T is C, U is C and W is C, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is N and is in the para position with respect to Z, Y is C, X is N, T is C, U is C and W is C, which can be used as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is N and is in the meta position with respect to Z and is in the para position with respect to the bond linked to NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is N and is in the meta position with respect to Z and is in the para position with respect to the bond linked to NR″, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is C, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the meta position with respect to Z and in the ortho position with respect to the bond linked to NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the para position with respect to Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the para position with respect to Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the meta position with respect to Z and is in the ortho position with respect to the bond linked to NR″, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes a compound, wherein Z is N, V is C, Y is C, X is C, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to one preferred aspect, formula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, formula (I) as defined above includes a compound, wherein Z is N, V is N and is in the para position with respect to Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, formula (I) as defined above includes a compound, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, formula (I) as defined above includes a compound, wherein Z is N, V is C, Y is C, X is C, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.

The compounds described herein may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids.

The compounds of formula (I) can include physiologically acceptable acid addition salts such as hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.

The compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the compounds describe herein can include all such solvates.

In the context of the present disclosure, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or         iodine, and in particular denotes chlorine, fluorine or bromine,     -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃         normal, secondary or tertiary saturated hydrocarbon. Examples         are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,     -   “(C₁-C₃)alkoxy” as used herein respectively refers to         O—(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.         Examples include, but are not limited to, methoxy, ethoxy,         1-propoxy, 2-propoxy,     -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively         to alkyl group and alkoxy group as above-defined, the groups         being substituted by at least one fluorine atom. Examples of         perfluoroalkyl groups include, but are not limited to,         trifluoromethyl or perfluoropropyl.     -   “patient” may extend to humans or mammals. For example, the term         “patient” can include cats or dogs.

In one aspect, the compounds described herein include a compound of formula (Ia)

-   -   wherein:     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl         group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group,         a —NR₁R₂ group and a (C₁-C₃)alkoxy group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R is a hydrogen atom, a halogen atom or a group chosen among a         (C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a         —NR₁R₂ group,     -   R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ib)

-   -   wherein:     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a         (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a phenoxy group and a         (C₁-C₄)alkoxy group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is preferably 1 or 2,     -   n′ is as defined above and is preferably 1,     -   R′ is a hydrogen atom, a halogen atom or a group chosen among a         (C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ic)

-   -   wherein:     -   R independently represent a hydrogen atom or a group chosen         among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂         group, a —COOR₁ group, a —NO₂ group and a (C₁-C₃)alkoxy group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Id)

-   -   wherein:     -   R independently represents a hydrogen atom or a group chosen         among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a         (C₁-C₃)alkoxy group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In certain aspects, the compounds described herein include a compound of formula (Ie)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R is a hydrogen atom, a halogen atom or a group chosen among a         (C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In another aspect, the compounds described herein include a compound of formula (If)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ig)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom or a halogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ih)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ii)

-   -   wherein:     -   R independently represents a hydrogen atom or a group chosen         among a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (ID

-   -   wherein:     -   R independently represents a hydrogen atom or a group chosen         among a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ik)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Il)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Im)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Io)

-   -   wherein:     -   R independently represent a hydrogen atom or a halogen atom or a         group chosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl         group, said alkyl being optionally mono-substituted by a         hydroxyl group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl         group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ip)

-   -   wherein:     -   R represents a hydrogen atom,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Iq)

-   -   wherein:     -   R independently represents a hydrogen atom, a (C₁-C₃)alkoxy         group or a (C₁-C₃)fluoroalkoxy group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, a         N-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a         morpholino group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (Ir)

-   -   wherein:     -   R independently represents a hydrogen atom or a (C₁-C₃)alkyl         group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 1,     -   R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, a         morpholino group and a (C₁-C₃)alkoxy group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In one aspect, the compounds described herein include a compound of formula (lee)

-   -   wherein:     -   R independently represents a hydrogen atom, a (C₁-C₃)alkyl group         or a (C₁-C₃)fluoroalkyl group,     -   R″ is as defined above and is advantageously a hydrogen atom,     -   n is as defined above and is advantageously 1,     -   n′ is as defined above and is advantageously 2,     -   R′ is a hydrogen atom or a (C₁-C₃)alkyl group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

Among the previous defined families of compounds of formulae (Ia) to (Iee), some are more particularly preferred for their use as an agent for preventing, inhibiting or treating cancer. These preferred compounds particularly belong to formulae (Ia), (Ie), (Iq) and (Iee), as defined above or one of its pharmaceutically acceptable salts.

Accordingly, the portions below further relate to a compound chosen among compounds of formulae (Ia), (Ie), (Iq) and (Iee), and their pharmaceutically acceptable salts for use as an agent for preventing, inhibiting or treating cancer.

In certain aspects, the compounds described herein include a compound of formula (Ia)

-   -   wherein:     -   R independently represents a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a —COOR₁         group and a (C₁-C₃)fluoroalkyl group,     -   R″ is as defined above and more preferably is a hydrogen atom,     -   R₁ is as defined above,     -   n is as defined above,     -   n′ is as defined above,     -   R′ is a halogen atom, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy         group or a —NO₂ group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In certain aspects, the compounds described herein include a compound of formula (Ie)

-   -   wherein:     -   R represents a hydrogen atom or a (C₁-C₄)alkyl group,     -   R″ is as defined above and more preferably is a hydrogen atom,     -   n is as defined above,     -   n′ is as defined above,     -   R′ is a halogen atom,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In certain aspects, the compounds described herein include a compound of formula (Iq)

-   -   wherein:     -   R′, R″, n and n′ are as defined in formula (I), and     -   R is a (C₁-C₃)fluoroalkoxy group,     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In certain aspects, the compounds described herein include a compound of formula (Iee)

-   -   wherein:     -   R is independently a hydrogen atom or a (C₁-C₄)alkyl group,     -   R′, R″, n and n′ are as defined in formula (I),     -   or one of its pharmaceutically acceptable salt,     -   for use as an agent for preventing, inhibiting or treating         cancer.

In certain aspects, the compounds described herein include a compound of formula (Ia) or (Ie) as defined above or one of its pharmaceutically acceptable salts, for use as an agent for preventing, inhibiting or treating cancer.

According to a preferred embodiment, the compounds described herein for use as an agent for preventing, inhibiting or treating cancer, is chosen from:

-   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine -   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid -   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine -   (4) Pyridin-2-yl-quinolin-2-yl-amine -   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid -   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine -   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile -   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine -   (9) Pyridin-2-yl-quinolin-3-yl-amine -   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine -   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine -   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine -   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine -   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid -   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine -   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine -   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine -   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine -   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine -   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine -   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile -   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile -   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine -   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine -   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine -   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine -   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile -   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine -   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine -   (33) 2-(quinolin-2-ylamino)isonicotinonitrile -   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine -   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine -   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine -   (37) 8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine -   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine -   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine -   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile -   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine -   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine -   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine -   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid -   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine -   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine -   (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride -   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride -   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine -   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine -   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine -   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile -   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine -   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine -   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine -   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (59) methyl 6-(quinolin-2-ylamino)nicotinate -   (60) methyl 6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate -   (61) methyl 6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate -   (62) methyl 2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate -   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine -   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine -   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine -   (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine -   (67) methyl 6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate -   (68) 8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine -   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol -   (70) 8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine -   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine -   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine -   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine -   (74) 3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine -   (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine -   (76) N-(4-methoxyphenyl)quinolin-2-amine -   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine -   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine -   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (81) 1-N,     1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine -   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine -   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine -   (85) N-(4-nitrophenyl)quinolin-2-amine -   (86) N-(3-fluorophenyl)quinolin-2-amine -   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine -   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine -   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride -   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (91)     3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine -   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine -   (94)     8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium     chloride -   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine -   (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium     chloride -   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine -   (102) N-(4-phenoxyphenyl)quinolin-2-amine -   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (104)     8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine -   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine -   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine -   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine -   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine -   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine -   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine -   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine -   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine -   (113) N-(pyrazin-2-yl)quinolin-2-amine -   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine -   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine -   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine -   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine -   (118) N-(pyridin-3-yl)quinolin-3-amine -   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine -   (120) N-(pyridin-4-yl)quinolin-2-amine -   (121) N-(pyridin-4-yl)quinolin-3-amine -   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine -   (123) N-(4-methoxyphenyl)quinolin-3-amine -   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine -   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine -   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine -   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine -   (128) N-(pyrimidin-2-yl)quinolin-2-amine -   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine -   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine -   (131) N-(pyrazin-2-yl)quinolin-6-amine -   (132) N-(pyrazin-2-yl)quinolin-3-amine -   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine -   (134) N-(naphthalen-2-yl)pyridin-2-amine -   (135) N-(pyridin-2-yl)quinoxalin-2-amine -   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine -   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile -   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine -   (139) N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine -   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine -   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine -   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine -   (143)     4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine -   (144)     4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine -   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine -   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine -   (147)     4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine -   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine -   (149)     5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine -   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine -   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine -   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine -   (153) 6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine -   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine -   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine -   (156)     4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine -   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine -   (158)     N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine -   (159) N-(3-aminopyridin-2-yl)quinolin-3-amine -   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine -   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine -   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine -   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine -   (164) [2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol -   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine -   (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine -   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine -   (168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine     -   and their pharmaceutically acceptable salts.

Among the compounds described above, compounds (6), (18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110), (112), (143), (144) and (148) are of particular interest.

As discussed above, the compounds described herein include compound (6), (18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110), (112), (143), (144) and (148) or one of its pharmaceutically acceptable salts for use as an agent for preventing, inhibiting or treating cancer.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) and (Iee) can comprise one or more asymmetric carbon atoms. They can thus exist in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including the racemic mixtures, are encompassed within the scope of the present invention.

The compound of formula (I) and the derivatives thereof can include their pharmaceutically acceptable salts, which includehydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.

In certain aspects, the compounds described herein includes compounds of formula (Ig)

-   -   wherein:     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl         group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a         (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a         (C₁-C₃)alkoxy group,     -   n is 1 or 2,     -   n′ is 1 or 2,     -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   with the proviso that R and R′ are not simultaneously a hydrogen         atom,     -   and when n and n′ are 1 and R is a hydrogen atom then R′ is not         a —COOH group,     -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds of formula (If)

-   -   wherein:     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl         group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a         (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a         (C₁-C₃)alkoxy group,     -   n is 1 or 2,     -   n′ is 1 or 2,     -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds of formula (Ih)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

-   -   n is 1 or 2,     -   n′ is 1 or 2,     -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds of formula (Il)

-   -   wherein:     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl         group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a         (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a         (C₁-C₃)alkoxy group,     -   n is 1 or 2,     -   n′ is 1 or 2,     -   R is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   with the proviso that R and R′ are not simultaneously a hydrogen         atom,     -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds of formula (Im)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

-   -   n is 1 or 2,     -   n′ is 1 or 2,     -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl         group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂         group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,     -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   with the proviso that when n and n′ are 1 and R is a hydrogen         atom, R′ is not a chlorine atom,     -   or anyone of its pharmaceutically acceptable salt.

For simplification, the following compounds and their corresponding definitions are called “new compounds”.

In certain aspects, the compounds described herein includes compounds of formula (Ia), as such,

-   -   wherein:     -   R″ and n are as defined in formula (Ia),     -   n′ is 1,     -   R independently represent a hydrogen atom, a halogen atom or a         group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl         group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group,         a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,     -   R′ is a hydrogen atom or a halogen atom or a group chosen among         a (C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,     -   R₁ is a hydrogen atom or a (C₁-C₃)alkyl group:     -   with the proviso that     -   when R and R′ are not simultaneously a hydrogen atom,     -   when n is 1, R is not a methyl group in the ortho or para         positions with respect to Z, Z being N,     -   when R′ is a hydrogen atom, R is not a bromine atom or a         chlorine atom,     -   when R is a hydrogen atom, R′ is not a methyl or ethyl group, a         —COOH group, a COOC₂H₅ group or a bromine atom, said bromine         atom being in the ortho position with respect to the bond linked         to NR″,     -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present invention more particularly focuses on compounds of formula (Ia), as such, wherein,

-   -   R independently represents a hydrogen atom or a (C₁-C₃)alkyl         group,     -   R″ is as defined in formula (Ia),     -   R′ is a hydrogen atom, a halogen atom, a (C₁-C₃)alkoxy group or         a —NO₂ group,     -   n′ is 1,     -   n is 1,     -   with the proviso that     -   when n is 1, R is not a methyl group in the ortho or para         positions with respect to Z, Z being N,     -   or one of its pharmaceutically acceptable salt.

In this aspect the compounds described herein can include compounds of formula (Ia′), as such,

-   -   wherein,     -   R independently represents a hydrogen atom, a (C₁-C₃)alkyl         group, a (C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl         group,     -   R″ is as defined in formula (Ia),     -   n is 1 or 2,     -   or one of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds of formula (Ie)

-   -   wherein:     -   R, R, R″ n and n′ are as defined in formula (I),     -   with the proviso that     -   when R is a hydrogen atom, R′ is not a bromine atom,     -   or one of its pharmaceutically acceptable salt.

The compounds described herein further relate to a compound of formula (Iq) as defined above, as such

-   -   wherein:     -   R, R, R″ and n′ are as defined in formula (I),     -   n is 1 or 2,     -   with the proviso that     -   R′ and R are not simultaneously a hydrogen atom,     -   when R′ is a hydrogen atom, R is not a —NO₂ group or a —NH₂         group,     -   when n is 2 and R′ is a hydrogen atom, R is not a COOC₂H₅ group         or a chlorine atom,     -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds described herein include compounds of formula (Iq), as such, wherein

-   -   R′, R″, n and n′ are as defined in formula (I), and     -   R is a (C₁-C₃)fluoroalkoxy group,     -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds described herein include compounds of formula (Iq), as such, wherein

-   -   R, R″, n and n′ are as defined in formula (I), and     -   R′ is a —NR₁R₂ group,     -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl         group,     -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds described herein include compounds of formula (Iq), as such, wherein

-   -   R, R″, n and n′ are as defined in formula (I), and     -   R′ is a morpholinyl group, a morpholino group or a         N-methylpiperazinyl group,     -   or one of its pharmaceutically acceptable salt.

In a further aspect, the compounds described herein includes a compound of formula (Iee) as defined above, as such

-   -   wherein:     -   R, R″, n and n′ are as defined in formula (I),     -   or one of its pharmaceutically acceptable salt,     -   with the exclusion of the following compound

-   -   and with the exclusion of compounds wherein R is a —NO₂ group or         a —NH₂ group when R′ is a hydrogen or a methyl group.

Still according to this particular embodiment, the compounds described herein include compounds of formula (Iee), as such, wherein

-   -   R′, R″, n and n′ are as defined in formula (I), and     -   R is a (C₁-C₃)fluoroalkyl group,     -   or one of its pharmaceutically acceptable salt.

Among the compounds discussed above, compounds (1), (2), (5)-(8), (10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceutically acceptable salts are of particular interest.

As discussed above, the compounds described herein include compounds (1), (2), (5)-(8), (10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceutically acceptable salts, as such.

More preferably, compounds (143), (144), (149), (166), (167) and their pharmaceutically acceptable salts are of particular interest.

For example, the compounds described herein can include compounds (143), (144), (149), (166), (167) and their pharmaceutically acceptable salts, where the pharmaceutically acceptable salts include, but are not limited to, hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.

In certain aspects, the compounds described herein include compounds (143) and (144) and their pharmaceutically acceptable salts, which include, but are not limited to, hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.

The compounds described herein, e.g. compounds of formulae (Ia), (Ie), (Iq) and (Iee) and the specific compounds as listed above, are not only useful as agent for inhibiting, preventing or treating cancer but can also be useful for inhibiting, preventing or treating premature aging or progeria and for inhibiting, preventing or treating AIDS.

According to an aspect of the invention, the compounds may be useful to inhibit, prevent and/or treat diseases with premature aging and that are likely related to aberrant splicing of the nuclear lamin A gene. For example, such diseases may include Hutchinson Guilford Progeria Syndrome (HGPS), progeria, premature aging associated with HIV infection, muscular dystrophy, Charcot-Marie-Tooth disorder, Werner syndrome, but the diseases may also include atherosclerosis, insulin resistant type II diabetes, cataracts, osteoporosis and aging of the skin such as restrictive dermopathy.

The compounds described herein can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent a general method useful for preparing the compounds of the present invention and are not meant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme 1 below.

As appears in the scheme, two routes are available for recovering a compound of formula (I) according to the present invention.

The synthesis is based on a coupling reaction alternatively starting from a halogeno-bicycle of formula (III), wherein X, Y, W, T, U, n′, R′ and R″ are as defined above and X′ is a chlorine atom or a bromine atom or from a chloro-monocycle of formula (V), wherein Z, V, n and R are as defined above and X′ is a chlorine atom or a bromine atom.

According to route (A), the compound of formula (III) is placed in a protic solvent such as tert-butanol. The compound of formula (IV) is then added in a molar ratio ranging from 1 to 1.5 with respect to the compound of formula (III) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃ in a molar ratio ranging from 1 and 2, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in an amount ranging from 2 mol % to 10 mol % relative to the total amount of compound of formula (III), and in the presence of a catalyst, such as Pd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % to 10 mol % relative to the total amount of compound of formula (III). The reaction mixture can then be heated at a temperature ranging from 80 to 120° C., for example at 90° C. and stirred for a time ranging form 15 to 25 hours, for example during 20 hours under inert gas and for example argon. The reaction mixture can be concentrated under reduced pressure.

According to route (B) the compound of formula (V) is placed in a protic solvent such as tert-butanol. The compound of formula (VI) is then added in a molar ratio ranging from 1 to 1.5 with respect to the compound of formula (V) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃ in a molar ratio ranging from 1 to 2, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in an amount ranging from 2 mol % to 10 mol % relative to the total amount of compound of formula (V), and in the presence of a catalyst, such as Pd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % to 10 mol % relative to the total amount of compound of formula (V). The reaction mixture can then be heated at a temperature ranging from 80 to 120° C., for example at 90° C. and stirred for a time ranging form 15 to 25 hours, for example during 20 hours under inert gas and for example argon. The reaction mixture can be concentrated under reduced pressure.

The starting compounds of formula (III), (IV), (V) and (VI) are commercially available or can be prepared according to methods known to the person skilled in the art. The chemical structures and spectroscopic data of some compounds of formula (I) are illustrated respectively in the following Table I and Table II.

TABLE I (I)

Formula (Ia) 1

2

3

4

5

6

7

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

150

151

152

153

154

Formula (Ib) 8

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

155

156

157

158

Formula (Ic) 9

10

11

12

13

14

105

106

159

Formula (Id) 15

16

107

108

Formula (Ie) 109

110

111

112

113

114

115

116

117

Formula (If) 118

Formula (Ig) 119

120

Formula (Ih) 121

Formula (Ii) 122

123

Formula (Ij) 124

125

126

127

Formula (Ik) 128

129

130

Formula (Il) 131

Formula (Im) 132

Formula (Io) 135

136

137

138

139

140

141

160

161

162

163

164

165

Formula (Ip) 142

Formula (Iq) 143

144

166

167

Formula (Ir) 145

146

147

168

Formula (Iee) 148

149

TABLE II Ex Characterizations 1 MS (ESI) [M + H]⁺ = 256 2 ¹H NMR (300 MHz, D₂O) δ 8.31 (d, J = 5.1, 1H), 8.21 (d, J = 9.3, 1H), 7.60 (d, J = 7.5, 3H), 7.34 (dd, J = 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J = 9.1, 1H) MS (ESI) [M + H]⁺ = 266 5 MS (ESI) [M + H]⁺ = 300 6 ¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 8.8, 2H), 7.78 (dd, J = 7.7, 13.7, 2H), 7.46 (d, J = 8.9, 1H), 7.31 (t, J = 7.8, 1H), 6.86 (d, J = 4.3, 1H), 2.37 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61, 148.37, 147.32, 142.65, 137.52, 129.68, 129.47, 126.82, 125.06, 123.26, 118.36, 115.10, 113.31, 21.24. MS (ESI) [M + H]⁺ = 270 7 ¹H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 8.71 (d, J = 1.4, 1H), 8.62 (d, J = 8.9, 1H), 8.24 (d, J = 8.9, 1H), 8.17 (dd, J = 1.9, 8.9, 1H), 7.89-7.74 (m, 2H), 7.66 (dd, J = 7.9, 14.2, 2H), 7.42 (t, J = 7.3, 1H). ¹³C NMR (75 MHz, DMSO) δ 156.09, 152.40, 152.11, 146.24, 141.07, 137.83, 129.87, 127.67, 126.78, 124.50, 124.21, 118.04, 114.49, 111.67, 100.12. MS (ESI) [M + H]⁺ = 247 8 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9, 1H), 7.79 (d, J = 8.4, 1H), 7.65 (t, J = 7.7, 3H), 7.59 (dd, J = 7.1, 8.3, 1H), 7.31 (t, J = 7.0, 1H), 7.20 (d, J = 8.5, 2H), 6.88 (d, J = 8.9, 1H), 6.80 (s, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 153.88, 147.62, 144.35, 139.26, 138.11, 130.13, 127.65, 127.12, 124.43, 123.70, 122.20, 120.95, 112.25. MS (ESI) [M + H]⁺ = 305 10 ¹H NMR (300 MHz, CDCl₃) δ 9.10 (d, J = 2.5, 1H), 8.83 (d, J = 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J = 1.3, 5.0, 1H), 7.85-7.79 (m, 1H), 7.52 (pd, J = 1.5, 6.9, 2H), 7.33 (s, 1H), 7.04 (dd, J = 1.2, 7.9, 1H), 6.81 (dd, J = 5.1, 7.9, 1H), 3.95 (s, 3H) 11 MS (ESI) [M + H]⁺ = 290 12 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (d, J = 2.7, 1H), 8.86 (d, J = 2.5, 1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J = 2.7, 9.2, 1H), 8.08 (d, J = 8.5, 1H), 7.83 (d, J = 8.5, 1H), 7.71-7.63 (m, 2H), 7.57 (t, J = 7.4, 2H), 6.82 (d, J = 9.1, 1H) 13 ¹H NMR (300 MHz, CDCl₃) δ 8.83 (d, J = 2.6, 1H), 8.37 (d, J = 2.3, 1H), 8.00 (d, J = 8.2, 1H), 7.71 (d, J = 7.7, 1H), 7.59-7.51 (m, 1H), 7.46 (dd, J = 7.3, 15.1, 2H), 6.71 (d, J = 8.3, 1H), 6.67 (d, J = 7.4, 1H), 2.49 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 157.13, 154.59, 145.81, 144.43, 138.78, 134.54, 129.22, 128.86, 127.41, 127.27, 121.48, 115.41, 106.50, 24.18. MS (ESI) [M + H]⁺ = 236 14 MS (ESI) [M + H]⁺ = 266 15 MS (ESI) [M + H]⁺ = 290 16 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 4.2, 1H), 8.04 (dd, J = 4.7, 8.7, 2H), 7.92 (d, J = 2.4, 1H), 7.59 (dd, J = 2.5, 9.1, 1H), 7.47 (t, J = 7.8, 1H), 7.35 (dd, J = 4.2, 8.3, 1H), 6.87 (s, 1H), 6.81 (d, J = 8.2, 1H), 6.70 (d, J = 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M + H]⁺ = 236 18 ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 59.9, 2H), 7.76 (d, J = 8.6, 1H), 7.58 (t, J = 8.3, 2H), 7.42 (d, J = 7.8, 1H), 7.09 (t, J = 7.7, 1H), 6.95 (d, J = 8.7, 1H), 6.71 (d, J = 7.3, 1H), 2.38 (s, 3H) 21 ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.89 (d, J = 8.3, 1H), 7.79 (s, 1H), 7.63 (d, J = 8.0, 1H), 7.56 (d, J = 7.3, 1H), 7.38 (s, 1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J = 4.9, 1H), 2.44 (s, 6H) 22 ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 8.4, 1H), 8.28 (d, J = 5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76-7.70 (m, 1H), 7.62 (d, J = 8.0, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.32 (t, J = 7.4, 1H), 6.95 (dd, J = 5.1, 6.5, 1H), 2.45 (s, 3H) 23 ¹H NMR (300 MHz, CDCl₃) δ 8.64 (d, J = 8.4, 1H), 8.55 (d, J = 2.1, 1H), 8.03 (s, 1H), 7.90 (d, J = 8.5, 4H), 7.66 (t, J = 7.6, 1H), 7.44 (t, J = 7.6, 1H), 7.06 (s, 1H), 2.67 (s, 4H) 24 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (d, J = 8.9, 1H), 8.53 (d, J = 1.7, 1H), 7.94 (dd, J = 2.2, 8.9, 1H), 7.92-7.84 (m, 2H), 7.67 (d, J = 8.6, 2H), 7.65-7.58 (m, 1H), 7.40 (t, J = 7.4, 1H), 2.49 (s, 3H) 25 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 5.2, 1H), 8.10 (s, 1H), 7.90 (d, J = 8.8, 1H), 7.79 (d, J = 9.0, 1H), 7.66 (d, J = 2.2, 1H), 7.55 (dd, J = 2.3, 8.9, 1H), 7.39 (d, J = 9.0, 1H), 6.79 (d, J = 5.2, 1H), 2.42 (s, 3H) MS (ESI) [M + H]⁺ = 270 26 ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J = 8.3, 1H), 7.70 (d, J = 9.0, 1H), 7.64 (d, J = 8.9, 1H), 7.49 (t, J = 7.9, 2H), 7.40 (dd, J = 2.3, 8.9, 1H), 7.18 (d, J = 8.9, 1H), 6.68 (d, J = 7.4, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 270 27 ¹H NMR (300 MHz, CDCl₃) δ 9.17 (d, J = 2.5, 1H), 8.71 (s, 1H), 8.49 (dd, J = 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9, 2H), 7.74-7.64 (m, 1H), 7.48 (dd, J = 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H) 28 ¹H NMR (300 MHz, CDCl₃) δ 8.64-8.51 (m, 3H), 8.18 (d, J = 9.0, 1H), 7.93 (d, J = 8.4, 1H), 7.79 (d, J = 8.1, 1H), 7.73-7.64 (m, 1H), 7.51-7.41 (m, 1H), 7.00 (dd, J = 4.6, 8.2, 1H), 6.75 (dd, J = 4.6, 8.3, 0H) 29 ¹H NMR (300 MHz, CDCl₃) δ 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J = 8.2, 1H), 7.76 (dd, J = 6.6, 25.5, 2H), 7.38 (d, J = 7.2, 1H), 7.04 (d, J = 4.4, 1H) 30 ¹H NMR (300 MHz, CDCl₃) δ 8.46 (dd, J = 1.9, 5.0, 1H), 7.87 (dd, J = 2.0, 7.6, 1H), 7.82 (d, J = 7.3, 1H), 7.60 (t, J = 7.3, 2H), 7.43-7.33 (m, 1H), 6.90 (dd, J = 5.0, 7.6, 1H), 2.64 (s, 3H) 31 ¹H NMR (300 MHz, CDCl₃) δ 8.44 (d, J = 9.1, 1H), 8.17 (d, J = 4.8, 1H), 8.03 (d, J = 9.1, 1H), 7.78 (d, J = 8.4, 1H), 7.68 (d, J = 8.0, 1H), 7.62-7.54 (m, 1H), 7.39 (d, J = 7.3, 1H), 7.32 (t, J = 7.5, 1H), 6.82 (dd, J = 5.0, 7.3, 1H), 2.31 (s, 3H) MS (ESI) [M + H]⁺ = 236 32 ¹H NMR (300 MHz, CDCl₃) δ 8.23 (d, J = 8.5, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.9, 1H), 7.82 (d, J = 8.4, 1H), 7.62 (d, J = 8.3, 1H), 7.56 (d, J = 7.3, 1H), 7.50 (dd, J = 1.8, 8.5, 1H), 7.37-7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M + H]⁺ = 236 33 ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.32 (d, J = 5.0, 1H), 7.95 (d, J = 8.8, 1H), 7.84 (d, J = 8.3, 1H), 7.60 (dd, J = 7.4, 14.1, 2H), 7.32 (t, J = 7.5, 1H), 7.04 (dd, J = 5.0, 9.0, 2H) MS (ESI) [M + H]⁺ = 247 34 ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.45 (d, J = 8.6, 1H), 8.01 (d, J = 8.8, 1H), 7.87 (dd, J = 2.5, 8.5, 2H), 7.72-7.56 (m, 2H), 7.39 (d, J = 9.0, 2H) MS (ESI) [M + H]⁺ = 290 35 ¹H NMR (300 MHz, CDCl₃) δ 8.32 (d, J = 9.1, 1H), 8.07 (d, J = 4.8, 1H), 7.93 (d, J = 9.1, 1H), 7.59 (t, J = 7.9, 1H), 7.52 (d, J = 8.0, 1H), 7.36 (d, J = 7.2, 1H), 7.14 (t, J = 7.8, 1H), 6.77 (dd, J = 5.0, 7.3, 1H), 2.29 (s, 3H) MS (ESI) [M + H]⁺ = 270 36 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 7.2, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.9, 1H), 7.62 (d, J = 7.6, 1H), 7.53 (dd, J = 1.8, 8.6, 1H), 7.46 (d, J = 7.9, 1H), 7.12 (t, J = 7.8, 1H), 7.05 (d, J = 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M + H]⁺ = 270 37 ¹H NMR (300 MHz, CDCl₃) δ 9.08 (d, J = 8.5, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 8.1, 2H), 7.77 (d, J = 7.2, 1H), 7.62 (d, J = 7.6, 1H), 7.35-7.24 (m, 1H), 7.12 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 324 38 ¹H NMR (300 MHz, CDCl₃) δ 8.69 (d, J = 9.1, 1H), 7.97 (d, J = 9.1, 1H), 7.80-7.74 (m, 1H), 7.70 (d, J = 8.4, 1H), 7.59 (d, J = 8.0, 1H), 7.54-7.45 (m, 1H), 7.22 (t, J = 7.5, 1H), 6.87 (d, J = 7.9, 1H), 6.68 (dd, J = 5.0, 7.9, 1H), 3.73 (s, 3H) MS (ESI) [M + H]⁺ = 252 39 ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7, 3H) 40 ¹H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.12 (d, J = 2.3, 1H), 8.50 (d, J = 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.64 (t, J = 7.7, 1H), 7.45 (t, J = 7.8, 1H) 41 ¹H NMR (300 MHz, CDCl₃) δ 8.52 (dd, J = 2.8, 8.6, 1H), 8.35 (s, 1H), 8.15 (d, J = 2.3, 1H), 7.94 (d, J = 8.8, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (d, J = 7.8, 1H), 7.59 (d, J = 7.2, 1H), 7.50-7.40 (m, 1H), 7.33 (t, J = 7.4, 1H), 7.11 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 240 42 ¹H NMR (300 MHz, CDCl₃) δ 8.55 (d, J = 6.8, 1H), 8.01 (d, J = 8.9, 2H), 7.82 (dd, J = 9.1, 17.3, 2H), 7.69 (d, J = 8.0, 1H), 7.63 (t, J = 7.6, 1H), 7.37 (t, J = 7.5, 1H), 7.32-7.18 (m, 2H) MS (ESI) [M + H]⁺ = 290 43 ¹H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J = 4.1, 9.3, 1H), 8.31 (d, J = 2.9, 1H), 8.20 (d, J = 8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J = 8.9, 1H), 7.32 (t, J = 7.8, 1H) ¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32, 153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49, 126.86, 125.29, 125.14, 125.04, 123.36, 114.91, 113.36. MS (ESI) [M + H]⁺ = 274 44 ¹H NMR (300 MHz, CDCl₃) δ 11.09 (s, 1H), 8.78 (d, J = 9.0, 1H), 8.42 (dd, J = 1.9, 4.7, 1H), 8.28 (dd, J = 1.9, 7.8, 1H), 8.11 (d, J = 9.1, 1H), 7.73 (d, J = 7.5, 1H), 7.65 (d, J = 8.1, 1H), 7.27 (dd, J = 6.4, 9.2, 1H), 6.88 (dd, J = 4.8, 7.8, 1H) MS (ESI) [M + H]⁺ = 300 46 ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 8.3, 1H), 7.73 (d, J = 8.3, 1H), 7.57 (s, 1H), 7.51 (t, J = 7.9, 1H), 7.43 (t, J = 9.2, 2H), 7.17 (t, J = 7.4, 1H), 6.67 (d, J = 7.4, 1H), 2.36 (s, 3H), 2.28 (s, 3H) 47 ¹H NMR (300 MHz, MeOD) δ 8.99 (s, 1H), 8.76 (d, J = 9.2, 1H), 8.32 (d, J = 8.7, 1H), 8.22 (d, J = 8.6, 1H), 8.11 (d, J = 7.8, 1H), 8.01 (t, J = 7.1, 1H), 7.76 (t, J = 7.4, 1H), 7.55-7.43 (m, 2H) MS (ESI) [M + H]⁺ = 247 48 ¹H NMR (300 MHz, MeOD) δ 8.48 (d, J = 9.1, 1H), 8.40 (d, J = 6.7, 1H), 7.94 (d, J = 8.4, 1H), 7.90 (d, J = 7.8, 1H), 7.54 (t, J = 8.0, 1H), 7.38 (d, J = 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H) MS (ESI) [M + H]⁺ = 270 49 ¹H NMR (300 MHz, CDCl₃) δ 9.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.1, 1H), 7.87 (d, J = 8.9, 1H), 7.71 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.19 (t, J = 7.8, 1H), 7.05 (d, J = 8.9, 1H), 6.84 (d, J = 5.1, 1H), 2.76 (q, J = 7.6, 2H), 1.37 (t, J = 7.6, 3H) 50 ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7, 3H) 51 ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 8.7, 1H), 7.71 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H), 7.20 (t, J = 7.7, 1H), 7.02 (d, J = 8.8, 1H), 6.67 (s, 1H), 2.43 (s, 3H), 2.39 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.15, 153.17, 152.82, 150.16, 143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62, 114.47, 111.02, 24.13, 21.70. MS (ESI) [M + H]⁺ = 284 52 ¹H NMR (300 MHz, CDCl₃) δ 8.89 (d, J = 8.8, 1H), 8.05 (d, J = 8.8, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.8, 1H), 7.79 (d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.32 (t, J = 7.8, 1H), 7.13 (d, J = 8.8, 1H), 2.67 (s, 3H) 53 ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.33 (d, J = 5.7, 1H), 8.13 (d, J = 5.2, 1H), 8.00 (d, J = 8.8, 1H), 7.76 (d, J = 7.4, 1H), 7.60 (d, J = 8.0, 1H), 7.29 (d, J = 7.9, 1H), 7.07 (d, J = 8.9, 1H), 6.97 (d, J = 4.8, 1H) 54 MS (ESI) [M + H]⁺ = 250 55 ¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4, 1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.7, 3H) 56 ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4, 1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47 (s, 3H), 1.25 (dd, J = 7.5, 15.5, 3H) 57 MS (ESI) [M + H]⁺ = 253 58 MS (ESI) [M + H]⁺ = 314-316 59 ¹H NMR (300 MHz, CDCl₃) δ 8.91 (d, J = 1.7, 1H), 8.46 (d, J = 8.8, 1H), 8.28 (dd, J = 2.0, 8.8, 1H), 8.23 (s, 1H), 8.03 (d, J = 8.8, 1H), 7.88 (d, J = 8.3, 1H), 7.70 (d, J = 8.0, 1H), 7.67-7.58 (m, 1H), 7.38 (t, J = 7.4, 1H), 7.32 (d, J = 8.8, 2H), 3.91 (s, 3H) 60 ¹H NMR (300 MHz, CDCl₃) δ 8.94 (d, J = 8.9, 1H), 8.91 (d, J = 1.8, 1H), 8.37 (dd, J = 2.2, 8.8, 1H), 8.04 (d, J = 8.9, 2H), 7.77 (d, J = 7.5, 1H), 7.62 (d, J = 7.2, 1H), 7.30 (t, J = 7.8, 2H), 7.19 (d, J = 8.8, 2H), 3.92 (s, 3H) 61 ¹H NMR (300 MHz, CDCl₃) δ 8.96 (d, J = 8.8, 1H), 8.85 (d, J = 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J = 8.0, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4, 2H), 7.53 (d, J = 8.4, 1H), 7.31 (t, J = 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H) MS (ESI) [M + H]⁺ = 294 62 ¹H NMR (300 MHz, CDCl₃) δ 11.02 (s, 1H), 8.75 (d, J = 9.2, 1H), 8.44 (d, J = 3.7, 1H), 8.31 (d, J = 7.9, 1H), 8.10 (d, J = 9.0, 1H), 7.72 (d, J = 7.5, 1H), 7.64 (d, J = 8.2, 1H), 7.27 (d, J = 8.1, 1H), 6.88 (dd, J = 4.7, 7.8, 1H), 3.97 (s, 3H) MS (ESI) [M + H]⁺ = 314 63 MS (ESI) [M + H]⁺ = 266 64 ¹H NMR (300 MHz, DMSO) δ 10.38 (s, 1H), 8.56 (s, 1H), 8.28 (d, J = 9.1, 1H), 8.20-8.03 (m, 3H), 7.50 (d, J = 8.7, 1H), 7.45 (d, J = 8.0, 1H), 6.88 (d, J = 4.4, 1H), 2.37 (s, 3H) 65 MS (ESI) [M + H]⁺ = 314-316 66 MS (ESI) [M + H]⁺ = 250 67 ¹H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.83 (d, J = 2.3, 1H), 8.62 (d, J = 9.3, 1H), 8.24 (dd, J = 2.7, 9.1, 1H), 7.96 (d, J = 8.9, 1H), 7.81 (d, J = 7.8, 1H), 7.67 (t, J = 7.6, 1H), 7.45 (d, J = 11.2, 2H), 3.86 (s, 3H), 2.62 (s, 3H) MS (ESI) [M + H]⁺ = 294 68 ¹H NMR (300 MHz, CDCl₃) δ 9.57 (s, 1H), 8.44 (d, J = 4.8, 1H), 8.05 (d, J = 8.8, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.31 (t, J = 7.8, 1H), 7.19 (d, J = 4.3, 1H), 7.04 (d, J = 8.8, 1H) 69 ¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.71 (d, J = 7.5, 1H), 7.57 (d, J = 7.8, 1H), 7.40 (s, 1H), 7.25 (d, J = 10.2, 2H), 7.17 (s, 1H), 7.05 (s, 1H) 70 ¹H NMR (300 MHz, CDCl₃) δ 9.07 (d, J = 8.5, 1H), 7.97 (d, J = 8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H), 7.75 (dd, J = 1.1, 7.5, 1H), 7.62-7.55 (m, 1H), 7.31 (d, J = 7.6, 1H), 7.27 (t, J = 7.8, 1H), 7.08 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 274 71 MS (ESI) [M + H]⁺ = 274 72 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3, 1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.57 (d, J = 7.9, 2H), 7.52 (d, J = 7.1, 1H), 7.28 (t, J = 7.4, 1H), 2.74 (q, J = 7.6, 2H), 2.42 (s, 3H), 1.31 (t, J = 7.6, 3H) MS (ESI) [M + H]⁺ = 264 73 ¹H NMR (300 MHz, CDCl₃) δ 8.91 (dd, J = 3.8, 9.0, 1H), 8.11 (d, J = 2.9, 1H), 7.81 (d, J = 8.3, 1H), 7.71 (s, 1H), 7.56 (dd, J = 7.4, 14.1, 2H), 7.51-7.42 (m, 1H), 7.29 (d, J = 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 254 74 ¹H NMR (300 MHz, CDCl₃) δ 8.96 (d, J = 8.3, 1H), 8.49 (s, 1H), 7.89 (dd, J = 1.9, 9.0, 1H), 7.82 (d, J = 8.2, 1H), 7.72 (s, 1H), 7.57 (t, J = 8.7, 3H), 7.33 (t, J = 7.4, 1H), 2.37 (s, 3H) MS (ESI) [M + H]⁺ = 304 75 ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J = 9.0, 1H), 7.69 (dd, J = 1.3, 7.6, 1H), 7.53 (dd, J = 1.2, 8.0, 1H), 7.42 (d, J = 8.9, 2H), 7.15 (t, J = 7.8, 1H), 6.89 (d, J = 8.9, 2H), 6.79 (d, J = 8.9, 2H), 2.97 (s, 6H) 77 ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J = 8.8, 1H), 7.70 (d, J = 7.6, 1H), 7.59 (d, J = 8.6, 2H), 7.52 (d, J = 7.3, 1H), 7.16 (t, J = 7.7, 1H), 6.94 (d, J = 8.4, 3H), 6.86 (d, J = 8.8, 1H), 3.82 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99, 126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74. MS (ESI) [M + H]⁺ = 285 78 ¹H NMR (300 MHz, CDCl₃) δ 7.80 (t, J = 7.6, 2H), 7.64 (d, J = 8.9, 2H), 7.61- 7.55 (m, 1H), 7.33 (t, J = 7.6, 1H), 7.19 (d, J = 8.7, 2H), 2.59 (s, 3H) 79 ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.4, 1H), 7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.57 (dd, J = 1.1, 8.0, 1H), 7.51 (ddd, J = 1.5, 7.0, 8.4, 1H), 7.29-7.21 (m, 1H), 6.96-6.90 (m, 2H), 3.82 (s, 3H), 2.35 (s, 3H) 80 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.53 (s, 1H), 2.42 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25, 143.86, 139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88, 120.44, 119.95, 17.77. MS (ESI) [M + H]⁺ = 319 81 ¹H NMR (300 MHz, CDCl₃) δ 7.75 (d, J = 8.3, 1H), 7.66 (d, J = 8.5, 3H), 7.55 (d, J = 7.8, 1H), 7.48 (t, J = 7.6, 1H), 7.20 (d, J = 7.2, 1H), 6.80 (d, J = 8.8, 2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35 (s, 3H) 82 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9, 1H), 7.82-7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59 (t, J = 7.6, 1H), 7.30 (dd, J = 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.84 (d, J = 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M + H]⁺ = 319 83 ¹H NMR (300 MHz, CDCl₃) δ 7.93-7.86 (m, 1H), 7.85 (s, 1H), 7.82 (d, J = 8.4, 1H), 7.59 (dd, J = 8.2, 15.5, 2H), 7.44-7.38 (m, 1H), 7.29 (dd, J = 8.3, 16.8, 2H), 6.91 (d, J = 9.0, 1H), 6.87 (d, J = 8.3, 1H) MS (ESI) [M + H]⁺ = 305 84 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 8.1, 1H), 7.92 (d, J = 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J = 7.6, 1H), 7.58 (d, J = 7.3, 1H), 7.30 (dd, J = 6.8, 14.8, 3H), 7.02 (t, J = 7.8, 1H), 6.89 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 305 86 ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J = 8.9, 1H), 7.83 (d, J = 8.3, 1H), 7.70 (d, J = 12.0, 1H), 7.61 (dd, J = 7.9, 18.1, 2H), 7.32 (d, J = 7.9, 1H), 7.31-7.25 (m, 1H), 7.21 (t, J = 6.5, 1H), 6.92 (d, J = 8.9, 1H), 6.79-6.68 (m, 1H) MS (ESI) [M + H]⁺ = 239 87 ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 7.76 (d, J = 8.9, 1H), 7.67 (d, J = 7.5, 1H), 7.51 (d, J = 8.2, 1H), 7.45 (d, J = 7.9, 1H), 7.28 (d, J = 8.2, 1H), 7.14 (t, J = 7.8, 1H), 6.86 (d, J = 10.1, 1H), 6.76 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 339 88 ¹H NMR (300 MHz, CDCl₃) δ 8.11 (dt, J = 2.1, 12.1, 1H), 7.76 (d, J = 8.9, 1H), 7.66 (dd, J = 1.2, 7.6, 1H), 7.45 (dd, J = 1.1, 8.0, 1H), 7.22 (dd, J = 1.4, 7.2, 2H), 7.18 (d, J = 7.6, 1H), 7.12 (d, J = 7.8, 1H), 6.75 (d, J = 8.9, 1H), 6.69 (d, J = 7.9, 1H) MS (ESI) [M + H]⁺ = 273 89 ¹H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 8.41 (d, J = 9.1, 1H), 7.93 (d, J = 7.8, 1H), 7.80 (dt, J = 8.1, 20.9, 4H), 7.50 (d, J = 7.8, 3H), 7.36 (d, J = 9.3, 1H) 90 ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 9.1, 2H), 7.79 (d, J = 8.9, 1H), 7.67 (dd, J = 1.2, 7.6, 1H), 7.48 (dd, J = 1.1, 8.0, 1H), 7.18 (s, 3H), 6.89 (s, 1H), 6.75 (d, J = 8.9, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25, 131.13, 130.13, 126.55, 125.42, 123.45, 122.50, 122.17, 120.49, 119.10, 113.24. MS (ESI) [M + H]⁺ = 339 91 ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.54 (s, 1H), 8.46 (d, J = 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67 (d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H) 92 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3, 1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.55 (dd, J = 7.5, 14.4, 2H), 7.29 (d, J = 7.8, 1H), 6.80 (d, J = 7.4, 1H) 93 ¹H NMR (300 MHz, CDCl₃) δ 9.21 (dd, J = 1.5, 8.4, 1H), 7.85 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.58 (d, J = 7.8, 1H), 7.53 (dd, J = 1.3, 8.3, 1H), 7.40-7.35 (m, 1H), 7.32 (dd, J = 1.1, 4.6, 1H), 7.31-7.24 (m, 2H), 7.04 (s, 1H), 7.02-6.94 (m, 1H), 2.38 (s, 3H) 94 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 8.7, 1H), 7.83 (d, J = 8.9, 1H), 7.63 (d, J = 7.6, 1H), 7.48 (d, J = 8.0, 1H), 7.13 (t, J = 7.8, 1H), 7.08 (s, 1H), 7.04 (s, 2H), 6.81 (d, J = 8.9, 2H), 2.27 (s, 3H) MS (ESI) [M + H]⁺ = 353 95 ¹H NMR (300 MHz, MeOD) δ 8.42 (s, 1H), 7.94 (d, J = 7.9, 1H), 7.83 (d, J = 8.1, 1H), 7.78 (d, J = 7.1, 1H), 7.72 (d, J = 8.7, 2H), 7.58 (d, J = 8.2, 3H), 2.60 (s, 3H) MS (ESI) [M + H]⁺ = 319 96 ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J = 8.9, 1H), 7.70 (d, J = 8.9, 1H), 7.64 (d, J = 8.9, 2H), 7.59 (d, J = 2.1, 1H), 7.50 (dd, J = 2.3, 8.9, 1H), 7.19 (d, J = 8.6, 2H), 6.85 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 281 97 ¹H NMR (300 MHz, MeOD) δ 8.11 (d, J = 8.4, 1H), 7.81 (s, 2H), 7.62 (d, J = 8.7, 3H), 7.51 (d, J = 8.3, 2H), 7.12 (s, 1H), 2.77 (s, 3H) MS (ESI) [M + H]⁺ = 319 98 MS (ESI) [M + H]⁺ = 383-385 99 MS (ESI) [M + H]⁺ = 320 100 MS (ESI) [M + H]⁺ = 316 101 ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J = 8.9, 1H), 7.70-7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84-1.68 (m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) MS (ESI) [M + H]⁺ = 327 102 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J = 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H), 7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H), 6.90 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 313 103 MS (ESI) [M + H]⁺ = 334 104 ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 2.5, 1H), 7.89 (d, J = 8.8, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (dd, J = 2.5, 8.9, 1H), 7.53 (d, J = 8.0, 1H), 7.23 (dd, J = 6.2, 14.0, 2H), 7.04 (s, 1H), 6.81 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 373 105 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (d, J = 2.6, 1H), 8.45 (d, J = 2.3, 1H), 8.01 (d, J = 8.1, 1H), 7.71 (d, J = 7.8, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6, 1H), 7.51-7.45 (m, 2H), 7.45-7.36 (m, 1H), 6.72-6.62 (m, 2H), 2.48 (s, 3H) 13C NMR (75 MHz, CDCl₃) δ 157.18, 154.80, 145.42, 143.80, 138.17, 135.04, 128.88, 128.76, 127.17, 127.04, 120.69, 115.22, 106.73, 24.38 106 ¹H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.06 (d, J = 2.3, 1H), 8.65 (d, J = 1.8, 1H), 8.60 (d, J = 8.3, 1H), 8.56 (d, J = 4.5, 1H), 7.97 (dd, J = 8.2, 14.4, 2H), 7.69 (t, J = 6.9, 1H), 7.59 (t, J = 7.4, 1H), 7.08 (dd, J = 4.6, 8.3, 1H) MS (ESI) [M + H]⁺ = 267 107 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 4.3, 1H), 8.06 (dd, J = 10.8, 18.4, 3H), 7.93 (d, J = 2.4, 1H), 7.57 (dd, J = 2.4, 9.0, 1H), 7.39 (ddd, J = 3.1, 8.3, 12.5, 3H), 6.93 (d, J = 8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 ¹H NMR (300 MHz, CDCl₃) δ 8.72 (dd, J = 1.6, 4.2, 1H), 8.61 (d, J = 2.4, 1H), 8.11 (d, J = 8.3, 1H), 8.00 (d, J = 9.0, 1H), 7.91 (dd, J = 1.2, 5.0, 1H), 7.69 (dd, J = 2.4, 9.1, 1H), 7.35-7.26 (m, 2H), 7.01 (dd, J = 1.2, 7.9, 1H), 6.77 (dd, J = 5.1, 7.8, 1H), 3.93 (s, 3H) 109 ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s, 1H), 8.21 (s, 2H), 7.94 (d, J = 8.9, 1H), 7.79 (d, J = 9.2, 1H), 7.67 (d, J = 2.3, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.34 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 257 110 1H NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.33-8.21 (m, 2H), 8.05 (d, J = 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J = 1.1, 7.8, 1H), 7.61 (s, 1H), 7.30- 7.22 (m, 3H), 7.16 (d, J = 8.8, 1H). MS (ESI) [M + H]⁺ = 301-303 111 ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J = 8.9, 1H), 7.70-7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84-1.68 (m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) 112 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J = 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H), 7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H), 6.90 (d, J = 8.9, 1H) ¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48, 142.18, 138.20, 137.55, 135.74, 129.71, 126.99, 125.35, 123.84, 114.75. MS (ESI) [M + H]⁺ = 255 113 ¹H NMR (300 MHz, CDCl₃) δ 9.74 (s, 1H), 8.20 (s, 2H), 8.03 (d, J = 8.6, 1H), 7.87 (d, J = 7.6, 1H), 7.80 (s, 1H), 7.70 (d, J = 8.0, 1H), 7.63 (t, J = 7.7, 1H), 7.37 (t, J = 7.4, 1H), 7.30 (d, J = 8.7, 1H) 114 ¹H NMR (300 MHz, CDCl₃) δ 9.67 (s, 1H), 8.34-8.12 (m, 2H), 7.84 (d, J = 8.0, 2H), 7.70-7.54 (m, 1H), 7.38 (t, J = 7.6, 1H), 7.17 (s, 1H), 2.61 (s, 3H) MS (ESI) [M + H]⁺ = 237 115 ¹H NMR (300 MHz, CDCl₃) δ 10.15 (s, 1H), 8.24-8.12 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.55 (t, J = 8.3, 2H), 7.30 (t, J = 7.9, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 237 116 MS (ESI) [M + H]⁺ = 240 117 MS (ESI) [M + H]⁺ = 253 118 MS (ESI) [M + H]⁺ = 222 119 MS (ESI) [M + H]⁺ = 256 121 MS (ESI) [M + H]⁺ = 222 124 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.95 (dd, J = 1.3, 8.2, 1H), 7.87-7.78 (m, 3H), 7.70-7.61 (m, 1H), 7.55-7.47 (m, 1H), 7.26 (dd, J = 2.4, 6.5, 3H), 6.90 (s, 1H) MS (ESI) [M + H]⁺ = 306 125 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.03 (d, J = 9.5, 1H), 7.92 (d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.61 (t, J = 7.3, 1H), 7.46 (t, J = 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126 ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.2, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (t, J = 7.4, 1H), 7.53 (d, J = 7.1, 1H), 7.48 (d, J = 7.2, 1H), 7.35 (t, J = 8.2, 1H), 7.22 (s, 1H), 6.94 (d, J = 8.1, 1H) 127 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (dd, J = 1.0, 8.3, 1H), 8.47 (s, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H), 7.72-7.61 (m, 1H), 7.57-7.47 (m, 1H), 7.42- 7.36 (m, 1H), 7.33 (d, J = 10.0, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H) 128 ¹H NMR (300 MHz, CDCl₃) δ 9.17 (s, 1H), 8.68 (d, J = 9.1, 1H), 8.64 (d, J = 4.8, 2H), 8.15 (d, J = 9.1, 1H), 7.87 (d, J = 8.4, 1H), 7.76 (d, J = 8.1, 1H), 7.64 (t, J = 7.7, 1H), 7.39 (t, J = 7.5, 1H), 6.87 (t, J = 4.8, 1H) ¹³C NMR (75 MHz, CDCl3) δ 158.34, 138.07, 129.85, 127.63, 127.31, 124.34, 114.20, 113.90. 129 ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.73 (d, J = 21.2, 3H), 8.17 (s, 1H), 7.73 (d, J = 20.3, 2H), 7.28 (d, J = 9.6, 2H), 6.91 (s, 1H) 130 ¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 8.64 (d, J = 4.8, 2H), 8.52 (s, 1H), 7.89 (dd, J = 8.5, 14.6, 2H), 7.63 (t, J = 7.5, 1H), 7.41 (t, J = 7.4, 1H), 6.86 (t, J = 4.8, 1H), 2.74 (s, 3H) MS (ESI) [M + H]⁺ = 237 132 ¹H NMR (300 MHz, CDCl₃) δ 8.86 (d, J = 2.6, 1H), 8.70 (d, J = 2.5, 1H), 8.32 (d, J = 1.1, 1H), 8.25-8.21 (m, 1H), 8.10 (d, J = 2.7, 1H), 8.06 (d, J = 8.3, 1H), 7.82 (dd, J = 1.2, 7.9, 1H), 7.66-7.51 (m, 3H), 6.89 (s, 1H) 135 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 8.71 (s, 1H), 8.54 (d, J = 8.4, 1H), 8.37 (dd, J = 1.0, 4.9, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H), 7.82-7.74 (m, 1H), 7.66 (t, J = 7.6, 1H), 7.52 (dd, J = 7.0, 8.1, 1H), 7.02 (dd, J = 5.0, 7.2, 1H) MS (ESI) [M + H]⁺ = 223 136 ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.20 (d, J = 5.1, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.64 (t, J = 7.6, 1H), 7.49 (t, J = 8.1, 1H), 6.83 (d, J = 5.0, 1H), 2.43 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55, 147.40, 140.93, 139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70, 113.75, 21.87. MS (ESI) [M + H]⁺ = 237 137 ¹H NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.03 (s, 1H), 8.82-8.75 (m, 1H), 8.56 (d, J = 8.9, 1H), 8.24 (dd, J = 2.3, 8.9, 1H), 7.96 (dd, J = 1.2, 8.2, 1H), 7.87 (dd, J = 1.0, 8.3, 1H), 7.79-7.71 (m, 1H), 7.61 (ddd, J = 1.4, 7.0, 8.3, 1H) MS (ESI) [M + H]⁺ = 248 138 ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.53 (s, 1H), 8.20 (d, J = 8.3, 1H), 7.93 (d, J = 8.2, 1H), 7.81 (d, J = 8.3, 1H), 7.62 (td, J = 3.4, 8.1, 2H), 7.53-7.43 (m, 1H), 6.83 (d, J = 7.4, 1H), 2.48 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.86, 152.27, 148.40, 140.92, 139.70, 139.00, 138.35, 130.42, 129.13, 127.14, 126.27, 117.76, 110.01, 24.15. MS (ESI) [M + H]⁺ = 237 139 ¹H NMR (300 MHz, CDCl₃) δ 8.53 (s, 1H), 8.20 (d, J = 4.8, 1H), 8.04 (d, J = 8.3, 1H), 7.92 (d, J = 8.4, 1H), 7.87 (s, 1H), 7.79 (t, J = 7.6, 1H), 7.60 (t, J = 7.6, 1H), 6.88 (d, J = 4.7, 1H), 2.46 (s, 3H) 140 ¹H NMR (300 MHz, CDCl₃) δ 9.93 (s, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.1, 1H), 7.99 (s, 1H), 7.82 (d, J = 8.2, 1H), 7.69 (t, J = 7.6, 1H), 7.59 (t, J = 8.2, 1H), 2.53 (s, 4H) 141 ¹H NMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 5.0, 1H), 8.05 (d, J = 7.7, 1H), 7.87 (d, J = 7.0, 1H), 7.66 (dd, J = 7.4, 16.9, 3H), 6.92 (d, J = 4.9, 1H), 2.58 (s, 3H) 143 ¹H NMR (300 MHz, DMSO) δ 8.85 (s, 1H), 8.42 (d, J = 5.3, 1H), 7.96 (d, J = 9.1, 1H), 7.44 (s, 1H), 7.30 (s, 4H), 7.28-7.21 (m, 2H), 6.66 (d, J = 5.3, 1H), 2.99 (s, 6H) ¹³C NMR (75 MHz, DMSO) δ 156.82, 150.25, 149.69, 143.79, 141.71, 125.95, 122.33, 118.88, 117.37, 115.95, 109.39, 104.92, 43.57 MS (ESI) [M + H]+ = 348 144 MS (ESI) [M + H]⁺ = 390 145 MS (ESI) [M + H]⁺ = 252 146 ¹H NMR (300 MHz, DMSO) δ 9.34 (s, 1H), 8.59 (d, J = 5.2, 1H), 8.53 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.98 (d, J = 9.0, 1H), 7.66 (d, J = 9.1, 1H), 6.80 (d, J = 5.2, 1H), 6.76 (s, 1H), 6.69 (d, J = 4.9, 1H), 4.00 (s, 3H), 2.26 (s, 3H) ¹³C NMR (75 MHz, DMSO) δ 161.31, 155.67, 151.63, 150.25, 147.77, 147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60, 111.41, 98.91, 55.78, 20.66. MS (ESI) [M + H]⁺ = 266 147 MS (ESI) [M + H]⁺ = 279 149 MS (ESI) [M + H]⁺ = 318 150 MS (ESI) [M + H]⁺ = 280 151 ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 8.04 (d, J = 8.3, 1H), 7.82 (d, J = 8.9, 1H), 7.74 (d, J = 8.9, 1H), 7.60 (t, J = 7.8, 2H), 7.50 (dd, J = 2.3, 8.9, 1H), 7.36 (d, J = 8.9, 1H), 6.79 (d, J = 7.4, 1H), 2.75 (q, J = 7.6, 2H), 1.30 (t, J = 7.6, 3H). MS (ESI) [M + H]⁺ = 284 152 ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J = 8.5, 1H), 8.08 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.77 (d, J = 8.9, 1H), 7.65 (d, J = 2.2, 1H), 7.55 (td, J = 2.0, 8.8, 2H), 7.39 (d, J = 9.0, 1H), 2.31 (s, 3H). MS (ESI) [M + H]⁺ = 270 153 ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J = 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67 (d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H). MS (ESI) [M + H]⁺ = 324 154 ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.12 (d, J = 8.4, 1H), 7.73 (d, J = 8.2, 2H), 7.66 (d, J = 10.0, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.82 (s, 1H), 5.10 (s, 2H), 2.16 (s, 4H). MS (ESI) [M + H]⁺ = 285 155 ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 8.3, 1H), 7.61 (s, 1H), 7.56 (d, J = 11.5, 2H), 7.44 (d, J = 8.3, 1H), 7.38 (d, J = 7.8, 1H), 7.13 (t, J = 7.4, 1H), 6.80 (d, J = 8.7, 2H), 3.85 (t, J = 6.5, 2H), 2.18 (s, 3H), 1.73-1.58 (m, 2H), 1.48-1.31 (m, 2H), 0.88 (t, J = 7.3, 3H) MS (ESI) [M + H]⁺ = 307 156 ¹H NMR (300 MHz, CDCl₃) δ 7.75 (d, J = 9.1, 1H), 7.62 (d, J = 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48 (dd, J = 2.4, 8.9, 1H), 7.30 (d, J = 8.9, 2H), 6.86 (d, J = 9.0, 1H), 6.77 (d, J = 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M + H]⁺ = 298 157 ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J = 2.6, 1H), 7.89 (d, J = 8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J = 2.6, 8.8, 1H), 7.55 (d, J = 7.8, 1H), 7.20 (t, J = 7.8, 1H), 6.95 (d, J = 8.9, 1H), 6.84 (d, J = 8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H) MS (ESI) [M + H]⁺ = 319 158 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 9.0, 1H), 7.70 (dd, J = 1.2, 7.5, 1H), 7.56 (dd, J = 1.1, 8.0, 1H), 7.30 (d, J = 8.6, 1H), 7.20 (t, J = 7.8, 1H), 6.71 (t, J = 5.9, 2H), 6.64 (d, J = 9.5, 1H). MS (ESI) [M + H]⁺ = 354 159 ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, J = 2.6, 1H), 8.37 (d, J = 2.6, 1H), 8.01 (d, J = 8.1, 1H), 7.91 (dd, J = 1.6, 4.9, 1H), 7.78-7.70 (m, 1H), 7.58-7.43 (m, 2H), 7.09 (dd, J = 1.6, 7.6, 1H), 6.84 (dd, J = 4.9, 7.6, 1H), 6.69 (s, 1H), 3.82-3.07 (m, 2H). 160 ¹H NMR (300 MHz, CDCl₃) δ 9.68-8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14 (d, J = 5.0, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.8, 1H), 7.61 (d, J = 8.5, 1H), 6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 ¹H NMR (300 MHz, CDCl₃) δ 9.98 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 5.2, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.63 (t, J = 7.5, 1H), 7.48 (t, J = 7.5, 1H), 6.87 (d, J = 5.0, 1H), 2.74 (q, J = 7.6, 2H), 1.34 (t, J = 7.6, 3H). MS (ESI) [M + H]⁺ = 251 162 ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s, 1H), 8.70-8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.1, 1H), 7.86 (d, J = 7.9, 1H), 7.68 (t, J = 8.2, 1H), 7.54 (t, J = 8.1, 1H), 2.49 (s, 3H) MS (ESI) [M + H]⁺ = 315 163 ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.2, 1H), 7.84 (d, J = 8.3, 1H), 7.64 (t, J = 8.2, 1H), 7.49 (t, J = 7.0, 1H), 6.69 (s, 1H), 2.45 (s, 3H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 251 164 ¹H NMR (300 MHz, DMSO) δ 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.24 (d, J = 3.0, 1H), 7.90 (d, J = 8.2, 1H), 7.79 (d, J = 8.3, 1H), 7.69 (t, J = 7.0, 1H), 7.52 (t, J = 7.4, 1H), 6.98 (d, J = 4.8, 1H), 5.45 (q, J = 5.6, 1H), 4.58 (d, J = 5.7, 2H). MS (ESI) [M + H]⁺ = 253 165 ¹H NMR (300 MHz, CDCl₃) δ 9.07 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 8.09-8.01 (m, 1H), 7.94 (d, J = 8.4, 1H), 7.81-7.71 (m, 1H), 7.69-7.59 (m, 1H), 2.80 (s, 3H) MS (ESI) [M + H]⁺ = 282 166 ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 5.0, 1H), 7.77 (d, J = 9.0, 1H), 7.32 (d, J = 2.0, 1H), 7.12 (d, J = 9.0, 2H), 6.99 (dd, J = 2.0, J = 9.0, 1H), 6.82 (d, J = 9.0, 2H), 6.57 (d, J = 5.0, 1H), 5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s, 4H), 2.62 (s, 4H), 2.34 (s, 3H) 167 MS (ESI) [M + H]⁺ = 335 168 MS (ESI) [M + H]⁺ = 321

The following examples illustrate in detail the preparation of compounds (51), (64), (110), (143) and (148) as described above. The structures of the products obtained have been confirmed at least by NMR spectra.

EXAMPLES

According to route (A), the compound of formula (III) is placed in a protic solvent such as tert-butanol. The compound of formula (IV) is then added in a 1.1 molar ratio with respect to the compound of formula (III) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃, in a 2.8 molar ratio, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in a 2 mol % amount relative to the total amount of compound of formula (III), and in the presence of a catalyst, such as Pd(OAc)₂ or Pd₂dba₃ in a 2 mol % amount relative to the total amount of compound of formula (III). The reaction mixture is then heated at 90° C., and stirred during 20 hours, under argon. The reaction mixture is concentrated under reduced pressure and the resulting residue is diluted with ethyl acetate. The organic phase is then washed twice with water, dried on magnesium sulphate, filtered and concentrated under reduced pressure. The residue could then be purified by column chromatography on silica gel to yield pure compounds (51), (64), (110), and (143).

According to route (B), the compound of formula (V) is placed in a protic solvent such as tert-butanol. The compound of formula (VI) is then added in a 1.1 molar ratio with respect to the compound of formula (V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence of Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol % amount relative to the total amount of compound of formula (V), and in the presence of a Pd(OAc)₂, in a 2 mol % amount relative to the total amount of compound of formula (V). The reaction mixture is then heated at 90° C., and stirred during 20 hours, under argon. The reaction mixture is concentrated under reduced pressure and the resulting residue is diluted with ethyl acetate. The organic phase is then washed twice with water, dried on magnesium sulphate, filtered and concentrated under reduced pressure. The residue could then be purified by column chromatography on silica gel to yield pure compound (148).

Example 1 Compound (51) of Table I

According to route (A), a mixture of 2,8-dichloroquinoline (98.5 mg) and 2-amino-4,6-dimethylpyridine (67.1 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (51) (99.7 mg).

Example 2 Compound (64) of Table I

According to route (A), a mixture of 2-chloro-5-nitroquinoline (100.0 mg) and 2-amino-4-methylpyridine (57.6 mg), Pd₂dba₃ (20 mg), XantPhos (30 mg) and K₂CO₃ (270 mg) in 3 mL of t-BuOH gave compound (64) (14.0 mg).

The preparation of 2-chloro-5-nitroquinoline is described in Patent application WO2009/23844.

Example 3 Compound (110) of Table I

According to route (A), a mixture of 8-bromo-2-chloroquinoline (500 mg) and aminopyrazine (216 mg), Pd₂dba₃ (95 mg), XantPhos (120 mg) and K₂CO₃ (1.15 g) in 12 mL of t-BuOH gave compound (110) (245 mg).

The preparation of 8-bromo-2-chloroquinoline is described in Cottet, F. et al. Eur. J. Org. Chem. 2003, 8, 1559.

Example 4 Compound (143) of Table I

According to route (A), a mixture of 7-chloro-4-(N,N-dimethylamino)quinoline (500 mg), 4-trifluoromethoxyaniline (0.257 mL), Pd₂dba₃ (110 mg), XPhos (115 mg) and K₂CO₃ (1 g) in 10 mL of t-BuOH gave compound (143) (410 mg).

The preparation of 7-chloro-4-(N,N-dimethylamino)quinoline is described in Sanchez-Martin, R. et al. J. Med. Chem. 2005, 48, 3354.

Example 5 Compound (148) of Table I

According to route (B), a mixture of 5,8-dimethylisoquinolin-6-amine (59 mg) and 2-bromo-5-methylpyridine (86 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (148) (48 mg).

The preparation of 5,8-dimethylisoquinolin-6-amine is described in Australian Journal of Chemistry 1969, 22, 2489.

1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.52 (d, J=6.0, 1H), 8.07 (s, 1H), 7.72 (d, J=6.0, 1H), 7.51 (s, 1H), 7.36 (dd, J=2.1, 8.4, 1H), 6.69 (d, J=8.3, 2H), 2.72 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H)

MS (ESI) [M+H]=264

Example 6 Pharmacological Data

Standard Operating Procedure:

Effect of drug compounds on invasion of MDA-MB231-D3H2LN cells into collagen

Background:

A key step in the generation of tumor metastasis is tumor cell invasion of the extracellular matrix, a major component of which is collagen. Therefore, the invasion of tumor cells into collagen in vitro may be indicative of tumor metastasis in vivo. E.g., MDA-MB231-luc-D3H2LN mouse breast cancer cells display both higher invasion into collagen in vitro and a higher metastatic potential in vivo as compared to MDA-MB231 cells (from which they were derived). Using these MDA-MB231-luc-D3H2LN cells as a model, the aim of the experiment described here is to identify drug compounds that inhibit the invasion of tumor cells into collagen in vitro, therefore potentially inhibiting also the generation of tumor metastasis in vivo.

Assay Principle:

Step 1:

Preparation of cells at the bottom of a collagen gel: Cells were suspended in a liquid collagen solution (4° C.), distributed into BSA-coated wells, and then collected at the bottom of the wells by centrifugation. The collagen was then solidified by incubation at 37° C. The BSA coating improves the adhesion of the collagen gel.

Step 2:

Pre-treatment with the compounds to be tested: Concentrated drug solutions were then added on top of the collagen, and cells are pre-incubated for 24 h with the drugs at low serum conditions (0.025% FBS).

Step 3:

Stimulation of invasion: Medium with 5% FBS was then added in order to stimulate invasion of the cells into the collagen gel.

Step 4:

Fixation and staining: Following another 24 h incubation, cells were fixed and nuclei were stained.

Step 5:

Analysis: Finally, plates were analyzed using an automated microscope. Fluorescent beads that have been included into the BSA coating serve to detect the bottom of the wells. Pictures of the stained nuclei were taken at the same level (0 μm) as well as 25 μm and 50 μm above.

Note:

In order to detect possible toxic effects, all compounds were tested in parallel in a viability assay. The viability assay was performed in parallel on serum-starved cells (as in the invasion assay) vs. cells under normal culture conditions (10% FBS).

Materials:

General Equipment:

Freezer (−20° C.), refrigerator (4° C.), ice machine, water bath (37° C.), incubator (37° C./5% CO₂), cell culture hood, vortex, vacuum pump, microscope, Malassez cell, Pipet aid, micropipettes (for pipetting 1-1000 μl), multichannel pipettes (for pipetting 20-200 μl), standard cell culture centrifuge, refrigerated centrifuge for 96 well plates.

General Consumables:

Sterile 96 well cell culture plates (for the viability assay), sterile tubes (1.5/15/50 ml), sterile pipettes (5/10/25 ml), sterile micropipette tips (for pipetting 1-1000 μl), sterile Pasteur pipettes, sterile reagent reservoirs.

General Products:

Sterile PBS, sterile Milli-Q water, DMSO, decomplemented FBS (frozen aliquots), 0.1 N NaOH, 1 M Hepes, MEM without serum (not older than 1 month), 2.5×MEM without serum (not older than 1 month), MEM with 10% FBS (not older than one month), 0.25% trypsin/1 mM EDTA solution, 37% formaldehyde solution.

Specific Equipment:

plate reader: Tecan Infinite F200

automated microscope: Cellomics ArrayScan VTI HCS Reader

Specific Consumables:

sterile black 96 well plates (for the invasion assay): Perkin Elmer ViewPlate-96 F TC, ref. 6005225

sterile 96 deep well polypropylene plates (for drug preparation): Starlab, ref. S1896-5110

Specific Products:

rat tail collagen, type 1: BD Biosciences, ref. 354236 (note: each new lot has to be validated)

red fluorescent beads (1 μm diameter): Invitrogen, ref. F13083

Y-27632 (5 mM aqueous solution): Calbiochem, ref. 688001 (in solution) or 688000 (dry powder)

BSA without fatty acids (sterile-filtered 4% aqueous solution): Sigma, ref. A8806 (dry powder)

Hoechst 33342 nuclear stain (10 mg/ml): Invitrogen, ref. H3570

MTS reagent: Promega CellTiter CellTiter 96® AQueous One Solution Reagent, ref. G3581

drug compounds to be tested: generally 25 or 50 mM in 100% DMSO (aliquots stored at −20° C., then at 4° C. for max. 3 months)

MDA-MB231-luc-D3H2LN cells:

Limits for the cell cultures to be used in the assays:

total passage number: max. 30

last passage: between 2 and 4 days before, between 1:3 and 1:20

cell density: between 50 and 90% (optimally 70%) (between 1 and 2×106 cells per 100 mm dish)

Experimental Procedures General Considerations

Controls and plate maps:

Invasion assay: Negative control: No drug (just DMSO at equivalent concentration). Positive control: 10 μM Y-27632. To avoid edge effects, only the 60 central wells B2-G11 were used; lines A and H as well as columns 1 and 12 remain free. Each drug was tested at least in triplicate. The positive and negative controls were tested in double triplicates at different positions on each plate. Typical plate map (−=negative control, +=positive control, 1-16=16 different drug compounds):

1 2 3 4 5 6 7 8 9 10 11 12 A B − 1 2 3 4 5 6 7 8 + C − 1 2 3 4 5 6 7 8 + D − 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 − F + 9 10 11 12 13 14 15 16 − G + 9 10 11 12 13 14 15 16 − H

Viability Assays:

No additional controls. The MTS viability assay was based on colorimetric detection of a product generated by the mitochondrial activity of the cells. Each drug was tested at least in duplicate. To detect potential direct interactions with the assay substrate, each drug was also tested in absence of cells (background signals). Typical plate map (controls and drug compounds as in the invasion assay, lines A-B and E-F: with cells, lines C-D and G-H: without cells; each 1 plate with 10% vs. 0.025% FBS):

1 2 3 4 5 6 7 8 9 10 11 12 A − 1 2 3 4 5 6 7 8 + B − 1 2 3 4 5 6 7 8 + C − 1 2 3 4 5 6 7 8 + D − 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 − F + 9 10 11 12 13 14 15 16 − G + 9 10 11 12 13 14 15 16 − H + 9 10 11 12 13 14 15 16 −

The volumes or other quantities indicated in the following are required for testing 16 drug compounds per 96 wells-plate at 5 μM each (+controls) in an invasion assay and each one viability assay on serum-starved cells vs. cells under normal culture conditions according to the plate maps above. According to the number of tested compounds, the volumes and other quantities should be adapted for testing more or less compounds or different concentrations.

Day 1: Preparation and Treatment of the Cells (all Steps are Performed Under a Cell Culture Hood):

Preparation of 100× concentrated drug solutions in 10% DMSO:

prepare 10% DMSO in sterile PBS: 1.8 ml sterile PBS+0.2 ml DMSO

prepare 100 μl/well 10% DMSO in PBS in 16 wells of a sterile 96 well polypropylene plate

add each 1 or 2 μl of the 50 or 25 mM compound stock solutions, respectively

mix by pipetting up and down

Preparation of 4× concentrated drug and control solutions in 0.4% DMSO in MEM+0.1% FBS:

Prepare MEM+0.1% FBS: 12 ml MEM without serum+12 μl FBS (freshly thawed aliquot)

prepare 48 μl/well MEM+0.1% FBS in 20 wells of a sterile 96 deep well polypropylene plate

negative controls (no drug): add each 20 μl 10% DMSO in sterile PBS

positive controls (Y-27632): add each 14 μl sterile PBS+2 μl DMSO+4 μl+5 mM Y-27632 (freshly thawed aliquot)

drug compounds: add each 20 μl of the 100× concentrated drug solutions in 10% DMSO

mix by pipetting up and down

store at RT until use

Coating of the Plates for the Invasion Assay:

mix 9.5 ml MEM without serum+0.5 ml 4% BSA without fatty acids+1 μl vortexed fluorescent beads (i.e. dilute 1:10000), vortex, distribute 100 μl/well into the plate for the invasion assay

centrifuge 30′ with 1800×g at 4° C. (e.g. 3000 rpm in a Jouan GR412 centrifuge)

remove supernatants by aspiration

Preparation of a 10×106 Cells/Ml Cell Suspension (During the Centrifugation of the Plates):

remove medium, wash cells with ˜10 ml/dish PBS, add 1 ml/dish 0.25% trypsin/1 mM EDTA

incubate 30-60 s at 37° C.

add 5-10 ml/dish pre-warmed MEM+10% FBS

homogenize by pipetting up and down using a 10 ml pipette, pool all

count cells using a Malassez cell

centrifuge 2×106 (or more) cells for 5′ with 150×g at RT (850 rpm in a std. cell culture centrifuge)

remove supernatant, resuspend cell pellet in 0.2 ml (or more, respectively) MEM without serum, yielding 10×106 cells/ml

Preparation of the Invasion Assay (on Ice; Start During the Centrifugation of the Cells):

mix on ice in a pre-chilled tube: example for a 3.4 mg/ml collagen stock solution; volumes of collagen and water to be adapted according to the stock concentration of each collagen lot:

2.8 ml 2.5×MEM

441 μl water

140 μl M Hepes

49 μl N NaOH

3.5 ml 3.4 mg/ml collagen stock solution (yielding 1.7 mg/ml collagen in 7 ml)

homogenize by pipetting gently up and down (keep on ice)

add 70 μl of the 10×106 cells/ml cell suspension, homogenize by pipetting gently up and down (yields 0.1×106 cells/ml in 1.7 mg/ml collagen in 7 ml 1×MEM+20 μM Hepes) (keep on ice)

distribute 100 μl/well (i.e. 10000 cells/well) into the coated wells of the plate for the invasion assay (all on ice)

centrifuge 5′ with 200×g at 4° C. (e.g. 1000 rpm in a Jouan GR412 centrifuge)

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂ (solidification of the collagen)

Preparation of the Viability Assay on Serum-Starved Cells:

add 50 μl of the 10×106 cells/ml cell suspension to 5 ml MEM without serum (yields 0.1×106 cells/ml)

distribute 100 μl/well of this suspension (i.e. 10000 cells/well) or MEM without serum without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂

Preparation of the Viability Assay on Cells Under Normal Culture Conditions:

add 30 μl of the 10×106 cells/ml cell suspension to 5 ml MEM+10% FBS (yields 0.06×106 cells/nil)

distribute 100 μl/well of this suspension (i.e. 6000 cells/well) or MEM+10% FBS without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂

Treatment with the Drugs:

add each 33 μl/well of the 4× concentrated drug solutions in MEM+0.1% FBS to the corresponding wells in all three plates, according to the plate maps above

incubate 24 h at 37° C./5% CO₂

Day 2: Addition of FBS to Stimulate the Invasion:

Microscopic Observation after 24 h of Treatment:

examine the cells of the viability assays

Addition of FBS (Under a Cell Culture Hood):

prepare MEM+5% FBS: 7.2 ml MEM without serum+0.8 ml FBS (freshly thawed aliquot or rest of the aliquot thawed the day before if kept at 4° C.)

add 33 μl/well to all wells of invasion and viability assays

incubate 24 h at 37° C./5% CO₂

Day 3: Stop:

Microscopic Observation after 48 h of Treatment:

examine the cells of the viability assays

Viability Assays: MTS Assay:

add each 33 μl/well of the MTS reagent, incubate 2.5 h at 37° C./5% CO₂

shake and read absorbance at 490 nm (proportional to the viability)

calculate the background-corrected signals by subtracting the means of the background signals in absence of cells from the corresponding signals in presence of cells

normalize the background-corrected signals with respect to the mean signal of the negative controls (no drug) (viabilities are thus expressed in “% of control”)

Invasion Assays:

fixation and staining (formaldehyde must be manipulated under a fume cupboard):

freshly prepare 1 μg/ml Hoechst 33342 in 18.5% formaldehyde: 5 ml PBS (not necessarily sterile)+5 ml 37% formaldehyde+1 μl 10 mg/ml Hoechst 33342 (note: for one plate, a smaller volume would be sufficient, but the minimal pipetted volume should not be below 1 μl)

add 50 μl/well to all wells of the invasion assay (yields 4.3% formaldehyde final)

seal with black film (provided with the plates)

incubate at least 7 h at RT

Day 3: 17 (Min 7 h/Max. 2 Weeks after Fixation and Staining): Analysis of the Invasion Assay:

Lecture using the Cellomics ArrayScan VTI HCS Reader:

BioApplication: SpotDetector.V3

Plate type: Perkin Elmer 96 well

Parameters of the Assay Protocol:

objective: 10× (NA 0.45)

apotome: yes (resulting optical slice: 11.7 μM)

fields per well: 8

autofocus in each field

autofocus channel: 1

channel 1 (autofocus on, and photo of the fluorescent beads at the bottom of the wells): filter: XF93-TRITC; exposure time: usually between 0.002 and 0.01 s

channel 2 (photo of the stained cells at the same level as the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: 0 μM

channel 3 (photo of the stained cells 25 μM above the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: −25 μM

channel 4 (photo of the fluorescent cells 50 μM above the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: −50 μM

object identification: method: fixed threshold: 100-32767

object selection parameters: min. max. SpotArea: 20 1000000000000 SpotShapeBFR: 0.2 1000 SpotShapeBAR: 0 1000 SpotAvgInten: 200 32767 SpotTotalInten: ≦4000 (thus 1000000000000 not limiting) TargetAvgInten: 0 32767 TargetTotalInten: 0 1000000000000

Analysis of the Results of the Scan Using vHCS Viewer:

export the results: for each well:

number of valid fields

number of objects in each valid field in each of the channels 2, 3 and 4 (“field details”)

mean numbers of objects per valid field for each well, in each of the channels 2, 3 and 4

exclude wells with less than 6 valid fields per well from further analysis

visually check all photos for any apparent problems, such as bad focusing or obviously inhomogeneous collagen structure (“bubbles”, . . . ), . . . ; in case of apparent problems: document, then exclude the corresponding wells from further analysis

Further Analysis of the Results of the Invasion Assay (Using e.g. Excel):

For each well, the mean invasion distance was calculated as follows: (25 μm×number of cells at 25 μm+50 μm×number cells at 50 μm)/sum of cells at 0, 25 and 50 μm

For all four parameters (number of cells at 0 μm, number of cells at 25 μm, number of cells at 50 μm, mean invasion distance of the counted cells), calculate means, SD and CV of the replicates (n=6 for the controls; n=3 for the samples).

Replicates having a CV ≧50% (compound to be re-tested, or assay to be repeated if CV ≧50% for the untreated negative control or the compound Y-27632-treated positive control) were invalidated. Y27632 is a selective inhibitor of the Rho-associated protein kinase p160ROCK of the following formula:

The assay was validated only if the mean invasion distance of the cells treated with 10 μM Y-27632 (positive control) was decreased by ≧40% as compared to the untreated negative control.

Graphs were plotted of all four parameters (number of cells at 0 μm, number of cells at 25 μm, number of cells at 50 μm, mean invasion distance of the counted cells).

Results

Anti-invasive effect at 5 μM on MDA-MB231 breast cancer cells (fold effect compared to 10 μM Y-27632 ref. compound)

Compound Invasion of MDA MB231 cells at 5 mM (family) (fold effect of positive control) 148 (Iee) 0.54 109 (Ie) 0.41 110 (Ie) 0.64 112 (Ie) 0.26 143 (Iq) 0.8 144 (Iq) 0.73 63 (Ia) 0.69 64 (Ia) 1.16 6 (Ia) 0.63 18 (Ia) 0.52 45 (Ia) 0.50 30 (Ia) 0.33 35 (Ia) 0.26 36 (Ia) 0.43 37 (Ia) 0.34 48 (Ia) 0.63 53 (Ia) 0.27 51 (Ia) 1.06 52 (Ia) 0.27 58 (Ia) 0.33 61 (Ia) 0.34 58 (Ia) 0.33 55 (Ia) 0.27 56 (Ia) 0.26

The compounds according to the present invention demonstrated an anti-invasive effect predictive for their activity against cancer.

Therefore, the results of the tests carried out with the compounds described herein demonstrated properties that may be useful to inhibit, prevent and/or treat cancer. For example, the following types of cancers may more be treated by the compounds according to the present invention: colorectal cancer, pancreatic cancer, lung cancer including non-small cell lung cancer, breast cancer, bladder cancer, gall bladder cancer, thyroid cancer, melanoma, liver cancer, uterine/cervical cancer, oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer, head and neck cancer, and stomach cancer, etc. For this purpose an effective amount of a said compound may be administered to a patient suffering from cancer.

The present disclosure is also related to the use of at least a compound chosen among a compound of anyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Ig), (Ir) or (Iee) as defined above, and compounds (1) to (168) as defined above, or one of its pharmaceutically acceptable salts according to the present invention for the manufacture of a pharmaceutical composition intended for the treatment of cancer.

The present disclosure also encompasses pharmaceutical compositions comprising at least a compound chosen among new compounds of formula (Ig) or (Iee) as defined above and compounds (143), (144), (149), (166) and (167) as defined above or any pharmaceutically acceptable salt thereof.

Thus, these pharmaceutical compositions contain an effective amount of said compound, and one or more pharmaceutical excipients.

The aforementioned excipients are selected according to the dosage form and the desired mode of administration.

In this context, the compounds described herein can be present in any pharmaceutical form suitable for enteral or parenteral administration, in association with appropriate excipients, for example in the form of plain or coated tablets, hard gelatine, soft shell capsules and other capsules, suppositories, or drinkable, such as suspensions, syrups, or injectable solutions or suspensions, in doses which enable the daily administration of from 0.1 to 1000 mg of active substance.

The present disclosure is also related to the use of a compound of anyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168) as defined above, or one of its pharmaceutically acceptable salts according to the present invention for the manufacture of a pharmaceutical composition intended for inhibiting, preventing and/or treating cancer.

The present disclosure further relates to a method of treatment of patients suffering from cancer, which comprises at least a step of administration to a patient suffering thereof of an effective amount of a compound of anyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ii), (Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above and (1) to (168) or one of its pharmaceutically acceptable salts. 

What is claimed is:
 1. A compound having the following formula or a pharmaceutically acceptable salt thereof:

wherein: R independently represent a hydrogen atom, a halogen atom, a —CN group, a hydroxyl group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group, or a (C₁-C₃)alkyl group optionally mono-substituted by a hydroxyl group, R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1, 2, or 3, n′ is 1 or 2, R′ is a hydrogen atom, a halogen atom, a (C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a morpholinyl group, a morpholino group, a N-methylpiperazinyl group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group, or a —CN group, and R″ is a hydrogen atom or a (C₁-C₄)alkyl group, with the proviso that: R and R are not simultaneously a hydrogen atom, when R′ is a hydrogen atom, R is not a —NO₂ group or a —NH₂ group, and when n is 2 and R′ is a hydrogen atom, R is not a COOC₂H₅ group or a chlorine atom.
 2. The compound of claim 1, wherein R is a (C₁-C₃)fluoroalkoxy group.
 3. The compound of claim 1, wherein R′ is a —NR₁R₂ group.
 4. The compound of claim 1, wherein is a morpholinyl, a morpholino group, or a N-methylpiperazinyl group.
 5. A compound selected from the group consisting of: (143) 4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine; (144) 4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine; (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine; (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine; and their pharmaceutically acceptable salts.
 6. The compound of claim 5, wherein the pharmaceutically acceptable salts are selected from hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.
 7. A pharmaceutical composition comprising at least one compound as defined in claim
 1. 8. A pharmaceutical composition comprising at least one compound as defined in claim
 2. 9. A pharmaceutical composition comprising at least one compound as defined in claim
 3. 10. A pharmaceutical composition comprising at least one compound as defined in claim
 4. 11. A pharmaceutical composition comprising at least one compound as defined in claim
 5. 12. A pharmaceutical composition comprising at least one compound as defined in claim
 6. 13. The pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable support.
 14. The pharmaceutical composition according to claim 8, further comprising a pharmaceutically acceptable support.
 15. The pharmaceutical composition according to claim 9, further comprising a pharmaceutically acceptable support.
 16. The pharmaceutical composition according to claim 10, further comprising a pharmaceutically acceptable support.
 17. The pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable support.
 18. The pharmaceutical composition according to claim 12, further comprising a pharmaceutically acceptable support.
 19. A method of preventing, inhibiting, or treating cancer, comprising: contacting a cell with at least one compound of formula (Iq) or a pharmaceutically acceptable salt thereof:

wherein: R independently represent a hydrogen atom, a halogen atom, a —CN group, a hydroxyl group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group, or a (C₁-C₃)alkyl group optionally mono-substituted by a hydroxyl group, R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1, 2, or 3, n′ is 1 or 2, R is a hydrogen atom, a halogen atom, a (C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a NR₁R₂ group, a morpholinyl group, a morpholino group, a N-methylpiperazinyl group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group, or a —CN group, and R″ is a hydrogen atom or a (C₁-C₄)alkyl group.
 20. The method of claim 19, wherein: R independently represent a hydrogen atom, a (C₁-C₃)alkoxy group, or a (C₁-C₃)fluoroalkoxy group, and R′ is a hydrogen atom, a —NR₁R₂ group, a N-methylpiperazinyl group, a (C₁-C₃)alkoxy group, or a morpholino group.
 21. The method of claim 19, wherein R is a (C₁-C₃)fluoroalkoxy group.
 22. A method of preventing, inhibiting, or treating cancer comprising contacting a cell with at least one compound selected from the group consisting of: (143) 4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine; (144) 4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine; (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine; (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine; and pharmaceutically acceptable salts thereof.
 23. The method of claim 22, wherein the pharmaceutically acceptable salts are selected from hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate, and fumarate.
 24. The method of claim 19, further comprising a step of administering the compound to a patient in need of cancer treatment.
 25. The method of claim 24, wherein the compound is administered to the patient orally.
 26. The method of claim 22, further comprising a step of administering the compound to a patient in need of cancer treatment.
 27. The method of claim 26, wherein the compound is administered to the patient orally. 